The aim of this work is to investigate the mechanisms controlling the expression of a multi-gene family, namely the class I MHC genes. The miniature swine has been chosen as an experimental model because there are only 7 members of the family, of which 6 have been isolated. Five have been extensively structurally characterized. To address the question of the molecular regulation of the expression of the class I MHC genes, two approaches have been taken: 1) analysis of in vivo patterns of expression of each of the genes in a variety of tissues both in the miniature swine and in transgenic mice containing only a single swine gene, and 2) characterization of regulatory elements associated with these genes. Three categories of MHC genes have been identified this way: 1) A set of closely related genes each of which are expressed in L cells and in nearly all swine somatic tissues, although at different levels. At least one of these genes is also expressed in a transgenic mouse with the same tissue distribution as in the swine. These genes encode products which are expressed on the cell surface and are able to bind a monoclonal antibody which recognizes a common determinant, also found on classical transplantation antigens. 2) A distantly related gene which is expressed both in L cells and in vivo but whose pattern of expression is distinct from that of transplantation antigens. 3) A set of genes which is expressed neither in L cells nor in vivo. Regulatory sequences within one of the transplantation antigen genes have been identified by generating a series of 5' end deletion mutants. The transcriptional promoter has been functionally identified as well as an interferon-responsive element. In addition, novel positive and negative regulatory sequence elements have been identified. It has been further shown that these elements function through the binding of transacting factors.